CN1306420A - Methods for treating capules and dry powdered pharmaceutical formulations - Google Patents

Abstract

The invention relates to a method for capsules used for storing a dry, powdered pharmaceutical formulation are extracted by supercritical fluids. The method is also used for removing undesirable material from drug powder. The amount of powder retained in the capsules following inhalation is minimized.

Description

Handle the method for the pharmaceutical preparation of capsule and dry powdery

The present invention is the contained not method of material in the relevant extractive capsule, and this capsule is to be used for storage and to keep the powdered drug preparation.Particularly, the present invention is the capsular method that relevant a kind of processing is used to store this powdered drug preparation, to reduce the not content of material (as: die lubricant or impurity) that may contain in the capsule.Die lubricant may be detained powderous preparations, and causes the inconsistent of active medicine dosage.The present invention is also about getting rid of the not method of material from drug powder or from form capsular material.Not material in the capsule can be the moisture content or the impurity that may contact with capsule 's content after after a while.At last, the present invention also relates to the capsule of processing according to the present invention.

Capsule contains the active medicine that can send the patient by inhalation to through being commonly used for the storage device of the fine drug powder of morcelling in this drug powder.For example: for avoiding using the propellant gas (chloro-fluoro-carbon or CFCs) of some hostile environments (destroying ozone layer in the atmosphere), the dried powder that will contain medicine is inserted in the capsule that utilizes dry powder inhaler (DPI) administration.Common this device cuts earlier before administration or punctures the capsule that contains dried powder, sucks powder by the patient then.

Capsule is made up of two half and half parts usually, generally by capsule manufacturer to be combination (driving fit) but non-locked state supply.Load between gleocystic stage, separately this two halves is loaded with the drug powder preparation that contains active medicine, then driving fit and sealed.Sealed capsule embeds among the DPI again.

Usually, capsule is the hard ' Yanming ' capsules for clearing.Also can use the hard fibre element and the plastic capsule that are suitable for storing drug powder.This capsule can be available from glue company (Capsugel) (Belgium) of card Soviet Union, Su Shen company (Su-Heung) (Korea S) and Yi Lanke company (Elanco) (U.S.), or the like manufacturer.

When if the active medicine in the powdered drug preparation will be sent to upper respiratory tract (being intranasal administration), the particle of active medicine should about 20 to about 100 microns sizes.If when active medicine will be offerd medicine to lower respiratory tract (promptly offeing medicine in lung), then the active medicine particle was preferably less than about 5 microns sizes.

There is operational issue (promptly loading capsule during manufacture) in this size, so active medicine mixes with more coarse grained carrier usually.Typical carriers is glucose, lactose or mannitol normally.In addition, the many medicines that are used for the suction treatment promptly be lower than about 250 micrograms, so this carrier also can be used as the extender of this medicine all with the low dose dispensing.Referring to for example: United States Patent (USP) 5,254,335.In addition, this carrier also can be used for improving the gas-dynamic flowability of preparation, so that dispersed particle during sucking.

Ipratropium bromide (Ipratropium bromide) is a kind of main active medicine via inhalation dosing (I.B.), and (Boehringer Ingelheim Pharmaceuticals is Inc.) with ATROVENT by Behringerl. Yin Gehaimu company ^Brand name listing.Because the dosage extremely low (＜50 microgram) of I.B., so the use of DPIs has problem.Therefore I.B. must mix with the extender as lactose or glucose, so that offer medicine via DPIs.

Make during the ' Yanming ' capsules for clearing, this capsular inner surface can be covered with one deck and release the mould lubricant.This is because relating to the mould bolt in this capsular manufacture process immerses in the capsule moulding material that has melted, by taking out the mould bolt in the capsule moulding material groove, the capsule moulding material is hardened on the mould bolt.And then on the mould bolt, take off hard capsule case.In order under not damaging, to take out capsule shells, must earlier lubricated mould bolt.This exactly lubricant can overlay on the capsular inner surface.And this lubricant may " glue pharmaceutical preparation " on capsule wall, causes active medicine to be trapped in the capsule and is not inhaled into.

Medicine is trapped in problem in the capsule more because the difference with every batch of capsule not only of the lubricant content in the capsule, and with each capsule in every batch and different complicated, when arriving medication amount (getting final product suction volume) the shortage repeatability of pulmonary, not only be attributable to contain lubricant, and owing to lubricant content in the capsule has sizable difference.Still can't control these factors easily between known manufacturing gleocystic stage.

In addition, can think that except powdered drug preparation or capsular water content, atmospheric humidity also may influence the concordance of active medicine dosage.This point may cause powderous preparations to be trapped on capsule wall and the surface.

Shown that lubricant is to make powder be trapped in the interior main reason of glutoid capsule.Brown S. (lark pharmaceutical factory, undocumented result, 1994) and afterwards Clark A.R. and Gonda I. (United States Patent (USP) 5,641,510) once illustrated this problem, and it uses the organic liquid solvent, extraction lubricant material in capsule.Brown clearly confirms, with an organic solvent during the lubricant on the eccysis capsule, can obviously reduce its hold-up.Yet, use this solvent but may introduce new impurity and solvent contamination, and can't under its closed state, process by capsule.The exceed oil mass of using of glue capsule manufacturer of another kind of possible solution is so that the capsule inner surface is reduced to minimum to the powder adsorbance.But the verified unreal border of this point.

Therefore, an object of the present invention is to develop a kind of method that reduces dry powdery pharmaceutical preparation residual quantity in the capsule.

Another object of the present invention is to reduce the difference that DPI provides active medicine content in the dosage.

Further object of the present invention is moisture content or the impurity of getting rid of in capsule and the powder activity pharmaceutical preparation.Other purposes of the present invention and advantage will be tangible to person skilled then.

The present invention proposes the residue problem of powderous preparations in the capsule with simple and Noninvasive mode.It provides a kind of new and novel method, make suck in the capsule of back the powder residual quantity reduce to minimum, thereby improve the active medicine amount that arrives patient pulmonary, improve its repeatability simultaneously.The present invention also provides a kind of method of controlling capsule moisture content.

Provide very big elasticity with lubricant material in supercritical liq (SCFs) extractive capsule to the course of processing.Content and the character of staying the part of not coming together of the lubricant material in the capsule can influence because of changing extraction time, pressure, temperature and/or pure SCF flow velocity, maybe can add a small amount of organic solvent to pure SCF, to improve or to reduce the solvent strength of SCF mixture.Opposite with the liquid flux extraction, this method also can extract the capsule that it is opening, driving fit or locked state, and does not have tangible physical change.Extraction driving fit formula capsular ability is very important, because the capsule that capsule manufacturer provides is closed state, and sends in the capsule loading machine with closed state, and therefore preferably extraction in this state simultaneously need not opened capsule again.

Now be surprised to find that, use SCFs replace organic solvent, aqueous solvent or solid matter to handle capsule, suck the residual of back capsule Chinese medicine and carrier with reduction, and the medication amount that DPIs is transmitted is higher and more consistent.Found the lubricant material that SCFs can selective extraction mainly causes medicine to be detained in opening, driving fit or sealed capsule.In addition, find that also SCFs also can be used for getting rid of trace impurity and the moisture content in capsule, medicine and the carrier particle, to reach more consistent surface nature, simultaneously to capsule or the unobserved injury of preparation.Found selective extraction lubricant material, thereby in the gas-dynamic particle size distribution of measuring powder and estimate to arrive capsule Chinese medicine anelasticity and minuteness particle quality in the used stepwise shock machine of the medication amount of pulmonary (particle＜5.8 micron) and have surprising positive effect.Having found can provide a kind of method of getting rid of most of adherent lubricant material with the SCFs extraction, the capsule inner surface is only stayed be close to solid to complete solid residue.Therefore this new method provides a kind of method of getting rid of the lubricant material composition that mainly causes the delay of capsule Chinese medicine, stay at the capsule inner surface and to be solid residue basically, make capsule surface more even and more consistent, found that identical technology can provide a kind of device that reduces the capsule water content, with reduce to similar before will filling DPI the degree of desired content.

Fig. 1 is the cell schematics that is used to implement the inventive method.

Fig. 2 is illustrated in exemplary dynamic supercritical liq extraction (SFE) experimental session pressure to scheme over time.

Fig. 3 represents that pressure is schemed over time in the capsular typical pressure swing SFE experiment.

Fig. 4 is the sketch map of Anderson (Andersen) particle size sampler II type (Mark II) that preseparator and inhaler are housed.

Fig. 5 is the sketch map that is equivalent to human respiratory system's the Andersen sampler stage.

Fig. 6 is the curve chart of the amounts of lubrication of SFE extraction to the time.

Fig. 7 is the curve chart of the amounts of lubrication of dynamic SFE extraction in two hours to pressure.

Fig. 8 is for mixing the HPLC chromatogram of drip washing solvent system.

Fig. 9 is the HPLC chromatogram of lubricant in the capsule.

Figure 10 be capsule of the present invention behind SFE, the HPLC chromatogram of lubricant residue in the capsule.

Figure 11 is sweep electron microscope (SEM) microphotogram of matched group capsule inner surface.

Figure 12 is the SEM microphotogram of the capsular inner surface handled through SFE according to the present invention.

Figure 13 represents matched group capsule Chinese medicine residual quantity and the disparity map between the drug residue in the capsule that SFE handles according to the present invention.

Figure 14 represents the medicine fine grain quality (FPM) of matched group capsule generation and the disparity map through between the medicine FPM that the capsule that SFE handles produces according to the present invention.

Figure 15 represent carrier residual quantity in the matched group capsule and according to the present invention in the capsule that SFE handles the disparity map between the carrier residual quantity.

Figure 16 represents the carrier FPM of matched group capsule generation and the disparity map through between the carrier FPM that the capsule that SFE handles produces according to the present invention.

Figure 17 is the diagram of explanation matched group capsule Chinese medicine residual quantity repeatability.

Figure 18 is the repeatability diagram that the capsule Chinese medicine residual quantity of handling through SFE according to the present invention is described.

Figure 19 is the diagram of the medicine FPM repeatability of explanation matched group capsule generation.

Figure 20 is the diagram that the medicine FPM repeatability of the capsule generation of handling through SFE according to the present invention is described.

Figure 21 represent matched group capsule Chinese medicine residual quantity and according to the present invention with the disparity map between the capsule Chinese medicine residual quantity of extensive extraction.

Figure 22 represents the disparity map between medicine FPM that the matched group capsule produces and the FPM that the capsule through extracting on a large scale produces according to the present invention.

Figure 23 is the diagram of explanation matched group capsule Chinese medicine residual quantity repeatability.

Figure 24 is the diagram of the explanation capsule Chinese medicine residual quantity repeatability that the extensive SFE of warp handles according to the present invention.

" capsule " speech in this article, be meant by following bushing type capsule dimerous: a main body and a diameter are big slightly, entangle the upper shield of its opening just.The powdered drug preparation that contains active medicine is inserted in the space by main body inner wall and upper shield form.This capsule is suitable for depositing the medical compounds with aerosol form dispensing patient usually." rigid " capsule represents that its hardness is enough to make drug powder to be deposited within it, and still can cut before use or pierce through, with drug powder that the patient is offerd medicine.

Suitable capsular example comprises rigid gelatin, cellulose and plastic capsule, and it mainly distinguishes fusion cellulose and plastic substance manufacturing by gelatin, but also for example can comprise: dyestuff, opacifying agent, plasticizer and antiseptic.

Capsule forms by carrying out the dip molding method in the film shaping solution usually.When making this capsule, use and release the mould lubricant promoting by forming capsular core splitting die bolt, thereby lubricant is then stayed on the capsular inner surface of half and half part.

" lubricant " is meant the material that can reduce the friction between mould bolt and the institute's moulding capsules inner surface.Lubricant can compatible with capsule (just would not decompose capsule), promotes that capsule separates with the mould bolt, and be pharmaceutically acceptable (avirulence just).Though lubricant can be single lubricant compound, it also can be a kind of " lubricant compositions " that contains one or more lubricant compound, and can optionally contain other additives or diluent.

Many examples of suitable lubricants be easy to get and can be used for making in the capsule.Available examples of lubricant comprises: silicone oil; Sodium lauryl sulfate or magnesium; Fatty acid (for example: stearic acid and lauric acid); Stearate (for example: magnesium stearate ,-aluminum or-calcium); Boric acid; Vegetable oil; Mineral oil (for example: paraffin); Phospholipid (for example: lecithin); Polyethylene Glycol; Sodium benzoate; And composition thereof.Usually also often contain other compositions in the lubricant.For example: calcium soap can be dispersed in the oil lubricant.Sometimes, lubricant for example is dissolved in: in the oil.This lubricant compositions is known in the prior art, therefore is included in " lubricant " speech.

" drug powder " is meant that comprising at least a active medicine reaches the selected in case of necessity pharmaceutically acceptable carrier or the powder of excipient when being used for the application's case.Drug powder is usually by offer medicine patient's respiratory tract of suction.The present invention is specially adapted to low-dose drugs.The average particle size of drug powder that contains medical preparation is preferably between 0.1 to 20 micron in the scope, and is better with 1 to 6 micron.Normally, the size of at least 50% particle drops in this scope.

The active medicine example in patient respiratory road of can offeing medicine comprises the medicament with antihistamine effect and anti-allergic effects, as: sodium cromoglicate, beta-2-agonists, anticholinergic agent as; Ipratropium bromide, Tiotropiumbromid (tiotropium bromide), bromination oxitropine (oxytropium bromide) and thiazine amide chlorine, sympatheticomimetic amine is as terbutaline (terbutaline), salbutamol (albuterol), Celenbuterol (clenbuterol), pyrrole butanols (pirbuterol), D-1959 (reproterol), procaterol (procaterol) and fenoterol (fenoterol), steroid, especially refer to corticosteroid, as beclomethasone (beclomethasone) dipropionate, and mucolytic agent is as NA-872 (ambroxol).Polypeptide also can be an active medicine, as: growth hormone, parathyroid hormone, thyrotropin, anticoagulin and lung surfactant, or the like.Usually polypeptide is to contain have an appointment amino acid whose peptide or protein more than 10.

Other may be applicable to that the active medicine example that adds in the rigid ' Yanming ' capsules for clearing comprises that sleeping pill, tranquilizer, tranquilizer, antibiotic medicine, antihistaminic, antitussive, anticonvulsant, muscle relaxant, spasmolytic, cardiovascalar agent, antibacterial agent are as pentamidine, antibiotic and Hypoylycemic agents.

Usually owing to relate to maneuver and the dosage of above once discussing, so drug powder comprises pharmaceutically acceptable carrier or excipient.For example: the physical mixture that can be formed by active medicine and carrier makes the fine active drug particle attached on sizable carrier particle.Perhaps, can form drug powder by the homogeneous mixture of active medicine particle and excipient.Pharmaceutically acceptable carrier or excipient example include, but is not limited to: salt compound (for example: sodium chloride) or sugar compounds (for example: glucose, fructose, lactose, mannitol, trehalose and sucrose).Sugar compounds can be crystallization, amorphous substance or its mixture.

If be necessary or when needing, can in drug powder, comprise other chemical compounds.For example: bronchodilator (for example: isoprenaline (isoprenaline), piperazine are breathed heavily rather (rimiterol), ephedrine (ephedrine), terbutaline diisobutyrate (ibuterol), neoisuprel (isoetharine), fenoterol (fenoterol), carbuterol (carbuterol), Celenbuterol (clenbuterol) or its pharmaceutically acceptable salt) or coloring agent or spice or antiseptic, as be usually used in joining in the dried powder inhalant compositions those, all can be contained in the drug powder.

" supercritical liq " is material or the mixture of substances that surpasses its critical temperature and critical pressure (SCF)." supercritical liq " speech also is used in reference to the liquid that is gas under the atmospheric condition and has medium critical temperature (promptly being lower than 200 ℃).As the SCF of carbon dioxide surpass its critical temperature and pressure (31 ℃, 1, in the time of 070psig), it shows as Compressed Gas.The solvent ability of the density of SCF and common SCF improves the solvent ability that reaches many organic solvents that increases with pressure.Yet,, and therefore have material from the faster conveying extraction of substrate (as: capsule) to main body CO because the gas property of SCF makes its characteristic with the diffusion coefficient that is higher than liquid ₂The ability of phase.Opposite with the extraction of liquid, SCF also discharges in extractor easily, and can not stay residue on the substrate (that is capsule) of extraction, and does not need further drying.The data of many relevant SCFs character, comprise similar when being used for making capsule the lipid material of lubricant at the dissolubility of SCFs, can from technical literature, obtain (McHugh M. and Krukonis, V, " supercritical liq extract, originality and maneuver (Supercritical FluidExtraction, Principles and Practice), the 2nd edition; Butterworths, 1993).

As CO ₂SCF have special affinity to being used for as the lipid material of the lubricant of Capsule demold, therefore be particularly suitable for this purposes.Yet as CO ₂SCFs have more extraction selectivity than most of organic solvents.Therefore be insoluble to CO ₂The lubricant composition be generally drying solid, and be not extracted, and stay on the capsule inner surface.This method is compared with the method that with an organic solvent extracts the lubricant material, and the latter almost can extract all lubricants, but stays residual solvent contamination thing in capsule.The present invention also can be used for extracting the lubricant that is dissolved in fully among the selected SCF or extracts under operating conditions such as the temperature that can extract all lubricants, pressure, flow velocity, extraction time and SCF modifier, can not stay any residual matter.It should be noted that according to the present invention the compositions that also can design a kind of lubricant material, make capsule after SFE handles, any residue all is appropriate combination thing and structure organization, and produces desired minimum residual quantity in capsule.This residual matter also can be used as and stops that moisture content diffuses into the barrier in the capsular content (being active medicine and excipient or carrier mass).Employed solvent or other solable matters stayed desciccate when the present invention also can be used for extracting the compounding pharmaceutical product in capsule.

Another obvious characteristic of the present invention is to be different from liquid flux, SCFs can be used for the opening capsule from sky, empty driving fit capsule or the sealed capsule of having filled extract lubricant, and can not stay any solvent contamination thing.

As CO ₂SCF can not change capsular color, outward appearance or physical property.Particularly, under certain conditions, CO ₂Can not extract any a large amount of active medicine or extender (as: lactose), therefore can not change under the preparation, from particle surface extraction trace impurity.In addition, found CO ₂Can provide a kind of dry capsule to being enough to reduce influence the method to minimum level of moisture content to drug residue.

The present invention determines that further the selective extraction of some lubricant compound does in order to a kind of, still less invasive and more easily method simpler, more effective than any other known method to be provided, to reduce the influencing to minimum level of lubricant material.Found that capsule and the interaction strength between medicine and the carrier particle that SCF extraction (SFE) produces are lower than without the capsule that extracts.In addition, this method can make capsule and medicine and carrier particle be dried to required degree, and can get rid of trace contaminant from medicine and carrier particle surface.

Work in-process of the present invention has bigger motility.Stay the content of the not lubricant material part of extraction in the capsule and the influence that character can be changed by extraction time, pressure, temperature or SCF flow velocity etc., or in SCF, add a small amount of organic solvent, to improve or to reduce the solvent strength of SCF mixture.Perhaps, also can use the CO that is supercritical form (gas or liquid) ₂Extract the lubricant material.

Therefore the present invention is a kind of novel method, is used for: 1. from capsule extraction lubricant material; 2. material is not wanted in extraction in capsule and content thereof; 3. make capsule be dried to required water content and brittleness; Reaching 4. removes impurity or does not want material in medicine and carrier particle.

This technology is different from aforementioned techniques, is Noninvasive (not introducing any new solid matter, liquid substance or impurity), does not stay any residual matter that records content, and without any need for further dry run.This method is design and expansion scale easily, and can finish in a few hours.It makes capsule not infringement and not change basically on outward appearance or color.

The present invention uses Noninvasive SCFs can significantly reduce residual medicine or the carrier amount in the capsule of back that suck in the mode of handling capsule surface, significantly increases the repeatability of DPI dosage and dosage simultaneously.The present invention is than the easier operation of technology (as: organic solvent extractionprocess) in the past, and can be used for handling: (1) opening capsule, be used for extracting the lubricant part that capsule part after the patient sucks medicine causes high drug residue, (2) Kong driving fit capsule, be used for opening capsule and can get rid of lubricant oils, (3) capsule of Tian Chonging, be used to extract lubricant oils (if capsule before the powder filler mixture not in advance when SCF extracts), employed solvent during the allotment medicine, or from the trace impurity of carrier or drug particle, (4) do not insert the medicine in the capsule or the impurity of carrier particle as yet, (5) capsule, carrier or drug particle, make it before the packing of product, just can reach required water content, or any combination of (6) these processing effects.In all purposes of the present invention, by CO ₂Or any other suitable SCF contacts with pending material, to implement lubricant, moisture content or the impurity in extractive capsule, carrier particle or the drug particle.The present invention can be used for the capsule of the goals of medicine that is useful on, and comprises the capsule of DPI and oral administration, and is not subjected to the influence of related medicine.

Carry out the original lubricant material of research and inquirement and from the extractibility of the lubricant of glutoid capsule.Adopt the extraction results of original lubricant material determine can be from the opening capsule condition of quantified extract lubricant.Capsule is to be its opening, driving fit or locked state, extracts by size of experiment.The capsule that is closed state amplifies scale to relatively large capsular feasibility also by extracting on a large scale to inquire into this method.Extensive extraction the results are shown in another joint.Medicine and carrier also are shown in another joint the influence of residual quantity and FPM.

Lubricant extract and residual matter use HPLC to analyze.Measure before the extraction and the capsule brittleness after the extraction, and adopt of the variation of sem analysis SFE method causing on the capsule surface.Adopt Anderson stepwise impacter (C.I.) to analyze the SFE-capsule of handling and the drug residue that capsule produced and the FPM that do not extract.Apparatus and method for

Adopt SFE unit the experimentizing property extraction experiments of building voluntarily.Extracting process and analytical method be exploitation voluntarily all.The amplification scale that confirms this method is implemented to be amplified in proportion by SFE specialized company to carry out.Following chapters and sections illustrative experiment SFE unit.Fairly large SFE unit is operated under similar principle.Experimental SFE equipment

As mentioned above, the present invention relates to use SCFs.Fig. 1 represents to can be used for to carry out for capsule or pharmaceutical preparation the experimental unitary flow chart of SFE, and it is a theme of the present invention.

Design SFE unit and flow process control and surveillance, and combination is from various different suppliers' element and equipment.Yet, the SFE unit also can available from ISCO company (Lincoln, NE) and use separation company (Applied Separations) (Allentown, PA).This unit is made up of three districts: feed zone 1-15, and extraction section, it comprises that the flow process parameter monitors and control 16-22, and flow measurement and extract recovery area 23-25.Employing is equipped with the computer 26 of data collection and control system and little proportional valve control system with the pressure in supervision and the control extraction container 19, and the temperature in the supervision extraction container and the flow velocity of the mass flow meter 25 of flowing through.Adopt the unit that is connected to tank 20 in addition to monitor and control its temperature.The SFE unit for example can be used for extracting medicine and/or carrier, original lubricant, from the lubricant in the sealed capsule of opening capsule, empty driving fit capsule or filling.The basic process of these usages is all similar.The capsular experimental SFE of drug powder, original lubricant or opening

The capsular general extraction process of drug powder, original lubricant or opening is as follows.Among Fig. 1, add known quantity and treat (high pressure equipment (HPE), Erie, PA, #GC-9 type) in extracting substance to the 350 milliliter high-pressure bottle 19.Closed container 19 tightly then, and insert thermostatic water bath 20 (Polyscience Niles, IL) in.Make container 19 and tank 20 reach thermal balance number minute then.

Adopt the carbon dioxide of various different purity to extract, comprise food-class CO ₂(lowest purity 99.2%), be used for the SCF chromatographic grade CO of this laboratory research ₂(lowest purity 99.9995%) or SFE level CO ₂(its impurity content can hang down and reach 10,000,000,000 (10 ¹²) divide 100.Make the CO in the gas cylinder 1 that ejector or siphon 2 and Pressure gauge 3 are housed then ₂Flow in the container, till pressure reaches about 900psig.Use the metathetical high-pressure pump 4 of forward (thermal release Products Co., Ltd) (Thermo SeparationProducts, Riviera Beach, FL, Model#396-89 type) then, by constant rate of speed pumping CO ₂, the pressure in extraction container reaches required degree.Make pump 4 heads coolings, for example, use circulating water chennel, the ethylene glycol solution of pumping-10 ℃ cools off.Perhaps use compressor pump gaseous state CO ₂This unit of flowing through.

The CO of pumping from gas cylinder 1 ₂Test valve 5 ((the Norwalk Valve ﹠amp of C valve and assembling company then flows through; Fitting (NV ﹠amp; F), Shelton, CT)), to avoid CO ₂Be back in the pump 4, if when producing excess pressure in the unit, have a rupture disc 16 (HPE) for this unitary content of safety dumping to ventilation slot, one or more decompress(ion) valve 7 (NV ﹠amp are arranged; F) control the CO that at first adds in the container 19 ₂Flow velocity, and shut off valve a 8 (NV ﹠amp was arranged before entering high-pressure bottle 19; F) and external diameter 1/8 " stainless steel hot exchange pipeline 15.The 21 initial maintenances of effluent shut off valve are closed, till container 19 internal pressures arrive required extracting pressure.When reaching required pressure, open effluent shut off valve 21, and little proportional valve 22 of flowing through (autoclave engineering company (Autoclave Engineers (AE)), the 30VRMM type) adopts Digitizing And Control Unit, the pressure converter 17 ((Omega of Omega company, Stamford, PX605 type) and be combined with the torque intensive of 50/1 gear ratio (all (CT)) stagewise motor (#M061-LE08 type) comes controlled pressure for Minarik CO, Bristol from Mi Na Riker Inc. CT).The common usage ratio formula-integration of pressure-derivative control figure is controlled at ± the 20psi scope in." thermocouple 18 (America and Europe adds company) monitors the temperature and pressure in the container 19 respectively in the bottoming hole of employing 5000psig Pressure gauge 16 (AE) and insertion high-pressure bottle 19 lids 1/16.

The CO that contains extract ₂Then expanding enters cold finger-type trap 24 by little proportional valve 22 and extracts, and by being close to pure CO ₂The electronic type of flowing through mass flow meter 25 (Omega (Omega) company, FMA1700 type) and delivering in the atmosphere.Fig. 2 illustrates pressure typical change in time in the SFE experiment.The dynamic extraction phase is meant when pressure is controlled at 2500psig, keeps CO simultaneously ₂Continue to flow through little proportional valve the time interval.

Adopt the effusive CO of 10psig decompress(ion) valve 23 dischargings ₂, and when producing excess pressure in the effluent pipeline, can use protection mass flow meter 25.When the dynamic extraction phase finished, pressure was slowly reduced to atmospheric pressure, discharged the not residue of extraction then in container, weighed and analyzed.The extract of intercepting and capturing in the effluent pipeline is discharged through the flushing of 60% ethanol/40%THF solution, merges with the extract that reclaims in the cold finger formula hydrazine 24, leaves in then in the amber bottle in the freezer, up to carrying out till HPLC analyzes.Capsule through extraction then leaves in the little aluminum bag, and sealing is till being used to analyze brittleness, powder residual quantity and fine grain quality.Gravimetry number of dropouts immediately after in container, discharging.The capsular SFE of driving fit

The purpose of extraction is for effectively getting rid of the contained CO that is dissolved in the capsule ₂In the lubricant material.Because driving fit capsule and main body CO ₂Mutually the mass transfer resistance is arranged, during according to traditional SFE (promptly the same, as under normal pressure, to carry out) extraction driving fit capsule, can't reasonably get rid of the lubricant that can extract in the capsule fully in the short-term extraction time with the opening capsule.Calculating by us shows, in 2 hours, and capsule CO ₂About 20% lubricant moves to main body CO in the phase inclusions ₂Mutually.In 5 hours dynamic extractions, about 55% capsule CO ₂Lubricant inclusions is mutually discharged outside the capsule.

Though have multiple technologies to can be used for improving the effect of extraction lubricant in the driving fit capsule, comprise increasing extraction time, pressure, temperature or CO ₂Flow velocity and use CO ₂As if make capsule bed fluidisation, the pressure oscillating method can effectively overcome the mass transfer barrier, it is a partially draining capsule contents when each pressure reduces.Therefore develop a kind of pressure oscillating method, partially draining capsule contents when each pressure reduces is to improve extraction efficiency.Therefore the capsular extraction of driving fit makes pressure sizable swing variation occur during being included in extraction.When carrying out this pressure oscillating extraction, make container rise to high pressure (for example: 2,500psig), in capsule batch extraction 5 minutes, slowly be depressurized to then than low pressure (1,500psig).Pressure afterwards makes CO ₂Density is than 2, the CO during 500psig ₂Density is almost low by 10%, but still enough high, and foot makes the material that comes together still be dissolved in capsule CO ₂Mutually.In the each pressure oscillating circulation of density decline 10% expression 10% capsule CO is arranged all ₂Lubricant is mutually discharged.Pressurize to 2 then, 500psig, and about 20 times of repetitive operation.When 20 pressure oscillating loop ends, capsule CO ₂Lubricant material concentration mutually low (＜initial concentration 7%) reduces pressure at last to atmospheric pressure, and the lubricant that all can be extracted is all discharged outside the capsule, and does not have lubricant material redeposition basically in capsule.This method promotes the CO in the capsule during pressure is rebuild ₂Mix mutually, improve lubricant thus and move to capsule CO by capsule surface ₂The mass transfer rates of phase, and impel the material discharge capsule that comes together to enter main body CO ₂Phase.Under this condition, our calculating shows in all extractable matters almost 100% discharges outside the capsule.Fig. 3 illustrates that the pressure that typical pressure oscillating SFE experimental session takes place changes.

Should be noted that upper pressure limit can raise on demand, but be preferably lower than 10,000psig, and its lower limit can reduce on demand.Decide according to lubricant concentration in the capsule and extraction conditions and method, also can change extraction phase required pressure oscillating number of times when the volume lubricant.The capsule brittleness

The capsule brittleness of employing before design can be measured the instrument that pierces through the required Impact energy of capsule to measure extraction and after the extraction.This instrument is made up of a pin that is connected the swing arm bottom basically, and this swing arm can be in the height swing and bump capsule that raise.The required energy of capsule is pierced through in minimum altitude decision during by bump needle-penetration capsule.Pierce through capsule institute energy requirement and heal when high, the capsule brittleness is lower.Capsular powder is loaded method

Preparation contains the mixture of powders of lactose and ipratropium bromide (I.B.).Confirm the uniformity of mixture of powders again by the HPLC method of analyzing medicine and carrier.5.5 milligram is by 5.454 milligrams of lactose and 0.046 milligram of mixture of powders that I.B forms.Mixture of powders is added in capsule and matched group capsule that SFE handles.For most of lactose is not inhaled in the lung, the powder particle size distribution should make the particle size of most of lactose quality greater than 5.8 microns.On the other hand, in order really to make the potential arrival of most of medicine patient pulmonary, the particle size distribution of I.B. should make the particle size of most of I.B. quality less than 5.8 microns.According to the capsule of size of experiment extraction is to load identical a collection of powder with artificial, and with the matched group capsule of artificial filling same powder relatively.The capsule of extensive extraction then utilizes technical grade capsule loading machine to load the same powder mixture of different lot numbers, and compares with the matched group capsule that utilizes same machines to load.The assembling of stepwise ram

Stepwise ram (C.I.) is the reference instrument of simulating human respiratory system.It is to be used for estimating the gas-dynamic medicine particulate ratio that may arrive lower respiratory tract (pulmonary) when the patient sucks medicine.Fig. 4 and 5 is Anderson (Andersen) C.I. diagrams, and particle size distribution among the explanation C.I., and each different piece of the corresponding human respiratory system of difference.C.I. (8 stage of the Anderson 1ACFM debility particle size sampler II (Mark II) that this research is used, (the Andersen Sampler of U.S. Anderson sampler company, Inc., Atlanta, Georgia, USA) preceding separator and inhaler are housed, it comprises interface and the capsule of having loaded, and through overcorrect, the magnitude range that makes per stage all as shown in Figure 5, it comprises a series of preceding separator stages and eight metal stages, and wherein the size of aperture is successively decreased from top to bottom, and is middle by collecting the metallic plate separation.

During operation, at first pierce through capsule, close inhaler with two prongs.Emit the button that pierces through then, adopt the sample a succession of stage of process in the vacuum pump sucking-off capsule.Particle more hour, the time of staying in the air-flow is longer, and can arrive the lower-order section.Enter in the air-flow in order to prevent particle from skipping the sublevel plate, therefore before reaching, collecting board is coated with adhesive material (glycerol that contains Brij35) BroadheadJ. on the separator, " dry powder inhaler: the effect (Dry Powder Inhalers:Evaluation of Testing Methodologyand Effect of Inhaler Design) of the assessment of test method(s) and inhaler design " Pharmaceutica Acta Helvetiae of Edmond Rouan S.K. and Rhodes C.T., 70,1995, pp.125-131).After each operation, the cleaning plank, and be coated with once again.After every operation 6 times, the preceding separator of coating once again.

Apparatus control system on C.I. reaches a period of time with the air by the inhaler inspiration.Fix on air velocity and sample time 28.3 liters/minute and 15 seconds respectively.Under this condition, when flow velocity is 2.35 meters ³/ hour and air pressure when being 1000hPa, the pressure that loses because of flow resistance is the 31cm water column.Again before interface uses the capsule of puncture to test.Adopt arm to determine that earlier the pressure of loss is still in the scope that can tolerate.

Measure fine grain quality in the 2nd to 7 stage of I.B. lactose pharmaceutical powder blend (as described above) residual quantity and C.I. in the capsule (FPM is promptly greater than＜5.8 microns mass particle), it approximates the medication amount of sending into patient pulmonary.The particle of collecting in the in the 0th to 1 stage is greater than 5.8 microns, and can't arrive the alveolar region of bronchioles or pulmonary.(part that its representative can suck (size＜5.8 microns) then uses 20 milliliters of 0.01N HCl to come together jointly to the particle of collecting from sublevel plate 2-7.This solution is again through 0.45 micron Ji graceful (Gelman) PTFE filter paper filtering.Adopt the amount in the HPLC mensuration sublevel plate 2 to 7 then, that is FPM.

The mensuration of the powder residual quantity in the capsule is by at first opening capsule, main body and upper shield are changed in 20 milliliters of screw-topped scinticounting bottles together with residual powder, add 10 milliliters of 0.01NHCl, sonication is 1 minute in ice bath, solution utilizes HPLC to analyze I.B. and lactose through 0.45 micron Ji graceful (German) PTFE filter paper filtering then.To every batch of capsule glue through extraction or matched group capsule all its residual quantity of replication and FPM at least 6 times.And the capsule of experimental scale extraction measured its residual quantity and FPM individually.To the capsule of extensive extraction, measure medicine and carrier residual quantity individually, on the ram plank, measure the FPM in each stage of ram with the deposit of 10 capsular merging.This kind practice can overcome the limit of HPLC analytic process detection sensitivity.The HPLC of lubricant oils analyzes

Employed lubricant kind is found through the HPLC chromatography when making this institute employing capsule, is mainly the free linoleic acid composition of lecithin.Therefore select the reference composition of linoleic acid for use as the lubricant content in the assessment inhalation capsules.In order to measure linoleic acid content in the original lubricant, the pure linoleic acid of injecting five kinds not commensurability (4 to 12 micrograms) and obtains calibration trace by peak district area to the linoleic acid injection volume to the HPLC system.Adopt 4.6 * 250 millimeters, the mobile phase of 5 microns Zorbax SB-phenyl posts (phenylcolumn) and 70/30 (v/v) acetonitrile/0.1% phosphoric acid is analyzed by 1.0 ml/min.Column temperature is due to 35 ℃, and volume injected is 25 microlitres, and UV detector wavelength is 210nm, 45 minutes operating times.

The mensuration of lubricant content is as follows in the capsule: at first, open 100 ' Yanming ' capsules for clearing, mix about 80 milliliters of ethanol/oxolanes (60: 40, v/v), about 5 minutes of sonicated in water-bath then.Extraction solution is moved in 250 milliliters of Pyrex vials carefully then.With about 40 milliliters of mixed extractant solvent capsule shells 2 times, extraction solution merges in the Pyrex vial again.The collection fluid is in N ₂Be evaporated to dried under the air-flow.Residual matter is dissolved in 5 milliliters of mixed solvent solutions.Solution filters through Acrodisc CR PTFE filter, analyzes filtrate with HPLC.According to amounts of lubrication on the linoleic acid amount assessment inside capsule wall of extractive capsule gained, the linoleic acid percentage ratio according to recording in the particular lubricants is converted into amounts of lubrication with the linoleic acid amount.The HPLC of medicine and carrier analyzes

I.B. analytic process is to adopt 4.6 * 150 millimeters Zorbax SB-C18 reversed-phase columns and is mobile phase with 0.008M1-sodium pentanesulfonate salt/acetonitrile 82: 18 (v/v), undertaken by the flow velocity of 1.5 ml/min.Column temperature is 35 ℃, and volume injected is 100 microlitres, and it is 210nm that UV detects wavelength, and the operating time is at least 10 minutes.

The analytic process of lactose is to adopt 7.8 * 300 millimeters Bio-Rad Aminex HPX-87H ion exclusion columns and is mobile phase with 0.012N sulphuric acid, undertaken by the flow velocity of 1.0 ml/min.Column temperature is 40 ℃, and volume injected is 100 microlitres, detects at least 15 minutes operating times under refraction coefficient.Capsular sweep electron microscope (SEM) microphotogram

Adopt sweep electron microscope (SEM, the S-4000 of Hitachi) to detect the variation that the SFE method causes the capsule inner surface.Utilize heating of metal silk cutting capsule, and use double faced adhesive tape viscosity elargol band that capsule is bonded on the aluminium bar.Sputter skim platinum on inner surface then.The SFE of original lubricant material

This experimental research is the original lubricant material that the extraction A of manufacturer is adopted when making capsule.Adopt these to study the condition of the lubricant material of judging in effective extractive capsule.

In this research, at first with the lubricant oils of known quantity to the little glass beaker of weighing in advance.Take by weighing the weight of beaker and oil then jointly, and add in the extraction container.In all experiments, bath temperature all remains on 35 ℃, CO ₂The flow velocity of pump is about 1.6SLM.After under this flow velocity 47 ± 2 minutes, pressure arrives 2,500psig, and subsequently in 2, about 1 times of volume of 2 hours commutative 350 ml containers of dynamic extraction under the 500psig.All operations is all selected 35 ℃ of temperature for use, because this temperature is a little more than CO ₂Critical temperature simultaneously should temperature also enough low, be enough to make CO ₂Rationally still keeping quite high density under the pressure, and can not make lubricant or gelatin mass produce thermal degradation.The lubricant quantity of all operations is 0.37 ± 0.01 gram, but in 2, except the operation 500psig under, its lubricant oils consumption under 2 hours dynamic extractions is 0.33 to restrain.After the extraction, by extracting preceding oil mass to staying the relative different calculated yield of the residual oil mass in the glass beaker.

Fig. 6 and 7 explanations are at different pressures condition and dynamic extraction under the time, with CO ₂The result of extraction lubricant.The two all influences yield Fig. 6 and 7 description times and pressure.Fig. 6 shows the extraction yield that increases with the dynamic extraction time; Yet 2, when 500psig surpassed 2 hours dynamic extraction down, the extraction yield did not significantly increase.2, when 500psig and 35 ℃, with CO ₂The maximum of extraction lubricant is 73.7%.Fig. 7 shows pressure by 2, and 500psig improves 4, and during 000psig, yield does not significantly increase.

Only when not in the dynamic extraction manipulate, (reach 2 in case just work as pressure, slowly get rid of container C O during 500psig ₂The operation of phase time), can between the pressure decrement phase, observe tangible lubricant precipitation.Fig. 6 explanation is worked as pressure and is at first arrived 2, and during 500psig, mainly the 25.6% lubricant material of partly being made up of lighter lubricant (94 milligrams of lubricant materials just) is dissolved in CO ₂Mutually.Therefore reach the maximum lubricant concentration of 0.26 mg/ml, this value is higher than capsule CO ₂The maximum lubricant concentration that may reach mutually (is that base is calculated as 0.13 mg/ml with 40 microgram capsule contents and 0.3 milliliter of capsule volume).This is illustrated in during the extractive capsule, if when capsule is not particularly limited mass transfer, in case pressure arrives 2, during 500psig, the more soluble lubricant part of great majority will appear at capsule CO ₂Mutually.

2, the oil residue that obtains in the experiment of 500psig and dynamic extraction time 〉=2 hour is similar solid glassy mass, then still is the similar liquids shape from the residue of other experiments, but bigger than pure lubricant oils viscosity.Therefore, in 2, following 2 hours dynamic extractions of 500psig should be basically and reclaim the lubricant that can extract in the capsule the most rightly, and almost extract all liq part in the lubricant, and this part is inferred to be the main cause that causes the capsule Chinese medicine residual.

Also inquired at CO ₂The middle influence of adding organic solvent to the more lubricants of extraction.In this research, at first get 30.8 milliliters of ethanol to container, add 0.38 gram lubricant oils then to glass beaker, the method for this interpolation modifier is different from the separately pumping modifier before adding to extraction container and makes it and CO ₂Blended method, the former is simpler, and can be used for guaranteeing contact lubricated dose CO ₂/ ethanol is unsaturation mutually or is close to saturated and supercritical.This extraction carried out under the 500psig 8 hours in 2, and guaranteeing when dynamic extraction finishes, nearly all ethanol is amount discharge container fully all.The HPLC of the extract that reclaims in cold-trap analyzes the response rate that the alcoholic acid existence of expression improves lubricant oils chemical compound (as: linoleic acid), but total response rate still is similar to the pure CO of use ₂In 2,500psig is 4 hours resulting response rate (73.7%) of extraction down.Therefore studies show that originally that in 2,500psig operates after 2 hours down, but should obtain the extraction oil of maximum recovery from capsule, and almost completely extract all liq part in the lubricant oils.

The capsule extraction is to reach extensive (250,000 capsules) at laboratory scale (experimental scale, 112 capsules), pilot-scale (9,000 capsules) simultaneously to carry out.Capsule extraction results when following chapters and sections explanation is amplified to 9,000 capsules scales.

The laboratory extraction of lubricant material in the capsule: to the influence of capsule weightlessness, brittleness, inner surface and medicine and carrier residual quantity and FPM

After the extraction, measure the residual quantity and the FPM of capsular weightlessness, brittleness and medicine and carrier.These results compare with each character of matched group capsule again.Processing conditions

The extraction of above-mentioned original lubricant is studied and be the analysis showed that, if adopt this to specify lubricant and above-mentioned extraction temperature and CO ₂During flow velocity, when reaching the soluble part of almost completely getting rid of in the lubricant, preferably should be 〉=2, extract the opening capsule under 500psig pressure and dynamic extraction time 〉=2 hour, and should adopt the extraction of pressure oscillating method the driving fit capsule.Really, we studies show that, in 2, the dynamic extraction time of 500psig and 1 hour is down during extraction opening capsule, compare with matched group (that is not extraction) capsule, have similar total capsule weightlessness (also being exactly the number of dropouts of moisture content+lubricant+other possibility impurity) and lower residual quantity, but then have higher residual quantity than 2 hours capsule of extraction under uniform pressure.This dynamic extraction deficiency of time that shows 1 hour is to get rid of the lubricant that can extract fully, and 2 hours extraction then is enough to reach the reinforcement of optimal capsule performance.Similarly, in 2, the dynamic extraction time of the constant voltage of 500psig and 2 hours is down during extraction driving fit capsule, the capsule that is produced also has with weight loss total like the matched group capsule class and is lower than the residual quantity of matched group, but the capsule that its medicine and carrier residual quantity are extracted far above the pressure oscillating method.Our conclusion is extraction moisture content and during some a spot of other extractable matters, can not reduces medicine and carrier residual quantity by any obvious mode except lubricant, and must be by capsule CO ₂The phase inclusions (is CO ₂+ lubricant) is transferred to main body CO ₂Phase (is close to pure CO ₂), so that reduce drug residue in a large number.Under felicity condition almost during extractive capsule (with 2, the dynamic extraction time extraction opening capsule of the pressure of 500psig and 2 hours and adopt pressure oscillating method extraction driving fit capsule), to the residual quantity of medicine and carrier and FPM to influence the result as follows.

Table 1 explanation is from the capsular extraction conditions of two tame different manufacturers.Single digital capsule lot number (1 to 4) is meant matched group batch.This research is used four batches from different manufacturers and the colored ' Yanming ' capsules for clearing of hard with different powder persistence characteristics." E " word table of capsule lot number back shows it is the extractive capsule of condition shown in the table 1.Capsule lot number 1 to 3 is general (promptly commercial) ' Yanming ' capsules for clearing from the A of manufacturer.4 general ' Yanming ' capsules for clearing by the B of manufacturer of capsule lot number are formed.Except capsule lot number 1 is that every other lot number capsule all is to extract by laboratory scale by outside pilot plant scale (about 9, the 000 capsules) extraction.All capsules that adopt in this C.I. research are all through artificial I.B./lactose powder mixture (as above-mentioned) of loading same batch.Table 1. is in 2, and 500psig, extracts the opening capsule and the capsular reference conditions of (2,500-1,500psig, 35 ℃) extraction driving fit under the pressure oscillating condition by 35 ℃ under 2 hours dynamic SFE

Matched group capsule lot number #	The capsule lot number # that SFE handles	Extraction	Gluey state	The capsular quality that is untreated (gram)	SFE handles capsular quality (gram)	Quality weightlessness (gram)	Quality weightlessness (%)
								????1	????1E	Pressure oscillating	Driving fit	????-	????-	?????-	?????-
????2	????2E1	Constant voltage	Opening	????5.31	????5.18	????0.13	????2.40
								????2	????2E2	Pressure oscillating	Driving fit	????5.24	????5.11	????0.12	????2.30
????3	????3E	Constant voltage	Opening	????5.24	????5.16	????0.08	????1.50
								????4	????4E	Pressure oscillating	Driving fit	????5.59	????5.58	????0.01	????0.20

-do not survey data

Most of capsule all designs the feature of ditch and projection, causes air pressure and the injury possible to capsule when avoiding capsule sealed.Think that these ditches can promote supercritical CO ₂The turnover capsule does not have the physical property injury; Yet when pressure formed with speed foundation quite slowly, the driving fit capsule can bear the SFE method.If when the foundation of first pressing was quite slow, all capsules all can extract by its closed state, and not damage.In the research, capsular color and the overall appearance handled through SFE all are similar to the matched group capsule.Capsule from lot number 4 is influenced by the SFE method least, and with operating condition and whether be opening, driving fit or even locked state extract all and have nothing to do.The opening capsule then is not subjected to the influence of SFE method.The capsules weight that runs off because of SFE

As shown in table 1, find all after each extraction that capsules weight reduces.The scope that weight runs off is big (0.2 to 2.4%) quite.Some weight of recovering easily when exposing to atmosphere yet this weight change only is equivalent to approximately that capsule is sent from container run off.General relative humidity (RH) before the extraction also influences the capsule water content, therefore can lose its relative weight because of SFE.

From the capsular weight loss excursion quite little (1.5 to 2.4%) of the A of manufacturer, when changing greatly may appear in relative humidity of atomsphere (RH) even experimental period reaches 5 months too.The weight number of dropouts of lot number 4 is minimum.Consequent result's effectiveness is confirmed in fairly large SFE (30,000 capsules) by lot number 4 that again wherein wt runs off and reaches 0.3%.Therefore as if lot number 4 contains minimum extractable matter (moisture content+lubricant+other extractable matters).Because the total amount few (＜4.5 milligrams) of lubricant in the capsule, so this weight loss (80 to 130 milligrams) obviously can not only extract owing to lubricant.

We have recorded all capsular moisture content absorption and desorption isotherm much at one; Promptly the isothermal line with the gelatin material equates; Therefore, viewed weight loss difference mainly should be owing to the general relative humidity difference before the extraction and the loss difference of the extractable matter except moisture content.For the influence of eliminating general atmosphere RH and measure the extractable matter proportion except lubricant and moisture content in the material, so the capsule of getting matched group lot number 2 and 4 is in the 53.3%RH environment, use Mg (NO ₃) ₂Saturated solution just extracts after adapting to 48 hours.Capsule is weighed subsequently, and with opening-like attitude, in 2,500psig extracted 2 hours down.Through the capsule of extraction adapts to 48 hours again in same solution after, weigh again once, not to run off by moisture content to cause to judge that this part weight runs off.Under this condition, lot number 2 and 4 weight run off and reach 0.52% and 0.45% respectively, and promptly the capsule of 46 milligrams of counterweights is respectively 239 micrograms and 207 micrograms.Therefore, before similar in the discovery result who does not regulate on the capsule that adapts to us, the extractable matter content in lot number 4 capsules except moisture content and lubricant is lower.

Get rid of bleeding of lubricant amount (its amount is 40 micrograms/capsules or lower) and disregard, these numbers of dropouts reach 170 approximately to 200 micrograms/capsules.This number of dropouts is if statistics goes up when effective, and is still considerably less, and be attributable to extracting substance as, organic impurities or low molecular weight gelatine material.The present invention also can be used as the method for impurity, solable matter or the fluidity substance (as: moisture) that may contact with mixture of powders or react in the extractive capsule substrate.Low molecular weight compound is a kind of mechanism that material not may contact mixture of powders by the diffusion of gelatin mass.Also can be used for extracting the impurity in the capsule of making by the material (as: plastic cement and cellulose) beyond the gelatin with quadrat method.The HPLC of capsule extract and residue

Fig. 8 and 9 is eluent solvent system (ethanol: THF) and use the chromatogram of the extract of this dicyandiamide solution extractive capsule.Lubricant comprises various different chemical compounds, comprises satisfied fatty acid, unsaturated fatty acid (comprising linoleic acid) and lecithin related substances.Figure 10 is the chromatogram of the lubricant residue in the capsule after the SFE extraction.The capsule drip washing near solvent peak time of being untreated goes out the lubricant compound of high concentration, but this does not appear in the residue.Untreated capsule several other compound concentrations that drip washing goes out in 4 to 14 minutes holdup time scopes are extremely low or do not observe in the capsule that SFE handles.Therefore these chemical compounds extract.In the residue these peaks the size and exist the obvious utmost point to be subjected to the condition influence of SFE method.Even these SFE extractions are adopted under the quite gentle SFE condition, also find to extract in the capsule linoleic acid composition up to 90%.Capsule brittleness behind the SFE

Table 2 explanation is high through the capsular brittleness that SFE handles than untreated capsule.This brittleness is similar to the brittleness that is reached through the power drying under the 21 ℃/22%RH, and this condition is to be used to reduce below the capsule water content to 12.4%, uses the exposure level that makes between moisture content and the drug powder and reduces to minimum.For some product, too much moisture content may cause particle aggregation, and the medicine molecular water is separated.Therefore the SFE technology also can be used for making capsule to reach this same dried degree.Table 2 pierces through matched group (being untreated) and in 2,500psig, 35 ℃ of power (millijoule) required when carrying out opening that SFE-handles and driving fit capsule

Lot number #	2(53.3％RH)	?3(53.3％RH)	?2E1	?3E	??2E1(53.3％RH)	?3E(53.3％RH)
							Power	????38	????42	?28	?32	????44	????48
	????36	????36	?21	?32	????44	????44
								????38	????34	?21	?24	????48	????48
	????46	????38	?24	?21	????48	????44
								????40	????44	?28	?21	????44	????48
	????36	????46	?17	?28	????44	????48
								????40	????40	?21	?28	????48	????36
	????46	????42	?32	?21	????44	????48
								????38	????38	?21	?28	????44	????48
	????40	????38	?32	?28	????48	????48
							Meansigma methods	????39.8	????39.8	?24.5	?26.3	????45.6	????46.0

Table 2 shows, regulates the matched group capsule that brittleness after adapting to is lower than adjusted adaptation slightly through capsule that SFE handles down in the 53.3%RH environment, but far below not regulating the capsule that adapts to but handle through SFE.This expression, the variation of the capsule brittleness behind the SFE is a reversibility, and mainly by CO ₂Getting rid of moisture content causes.Really, as if capsular color, engineering properties and the chemical property through extraction and adjusting adaptation is identical with the matched group capsule.The capsular low slightly brittleness of the SFE processing through regulating adaptation reaches through the viewed a small amount of capsules weight loss of the capsule of extraction (20 micrograms/capsules) and all points out, when the capsule of SFE processing was reached balance, the material that comes together may be replaced by moisture content.Capsular SEM

The SEM microphotogram of matched group capsule inner surface shows that the lubricant material is droplet-shaped, and is different contact angles with ' Yanming ' capsules for clearing and is distributed in the capsule.As if the lubricant droplet also present different sizes.On the other hand, any liquid lubricant material does not appear in the capsule of SFE processing.As if this surface dry, and owing to got rid of lubricant, so the lip-deep peak of gelatin is easily seen than matched group is more obvious with trench.Figure 11 and 12 these results of explanation.Medicine and carrier residual quantity and fine grain quality (FPM)

Table 3 shows that to 6 Anderson C.I. measures the result of medicine and carrier residual quantity and FPM.These results of Figure 13 to 16 graphic extension.Table 3 and 5 and Figure 13 and 15 show that capsular medicine and carrier residual quantity that SFE handles are lower than the matched group capsule, and be not subjected to manufacturer and capsule whether to be the influence of opening or closed state extraction.The capsule Chinese medicine residual quantity (microgram/capsules) that table 3. matched group capsule and SFE-handle

????F	??1	??1E	??2	?2E1	?2E2	???3	??3E	??4	??4E
										?1(n=6)	?6.21 ?11.11 ?6.68 ?9.95 ?8.58 ?6.08	?5.13 ?4.87 ?4.73 ?5.46 ?4.44 ?5.52	?7.29 ?6.77 ?9.21 ?9.15 ?8.05 ?8.27	?2.32 ?2.06 ?2.03 ?5.52 ?2.44 ?2.45	?1.90 ?3.69 ?3.39 ?3.51 ?2.96 ?2.50	?10.57 ?11.62 ?14.45 ???- ?9.90 ?14.83	?3.30 ?1.43 ?2.21 ?2.86 ?3.15 ?2.17	?2.66 ?2.23 ?4.91 ?7.80 ?5.95 ?5.70	?4.13 ?4.02 ?3.83 ?4.65 ?4.29 ?5.13
?2(n=6)		?4.79 ?5.20 ?3.39 ?4.07 ?3.97 ?4.62	?8.15 ?6.60 ?6.58 ?11.14 ?9.01 ?9.77	?1.80 ?2.20 ?1.85 ?2.36 ?1.30 ?1.55	?2.80 ?2.15 ?2.42 ?3.23 ?3.00 ?4.23	?10.57 ?10.47 ?13.27 ?7.96 ?6.66 ?8.18	?3.65 ?3.94 ?1.97 ?5.09 ?3.56 ?2.35
										?3(n=6)		?4.17 ?3.58 ?6.37 ?3.18 ?4.54 ?5.09	?9.77 ?8.14 ?8.75 ?5.34 ?7.61 ?7.09	?2.16 ?2.59 ?3.48 ?2.16 ?2.09 ?1.30	?3.16 ?2.61 ?3.58 ?4.11 ?2.86 ?4.23	?9.93 ?8.53 ?8.05 ?8.77 ?9.68 ?12.38	?2.78 ?2.70 ?2.92 ?5.02 ?4.18 ?3.21
Meansigma methods	?8.10	?4.62	?8.15	?2.31	?3.13	?10.34	?3.14	?4.88	?4.35
										Standard deviation	?2.1	?0.8	?1.4	?0.9	?0.7	?2.3	?1.0	?2.1	?0.5

The medicine fine grain quality (microgram/capsules) that capsule produced that table 4. matched group capsule and SFE-handle

Operation #	???1	??1E	???2	??2E1	??2E2	???3	???3E	???4	??4E
										?1(n=6)	?13.87 ?7.88 ?11.41 ?12.09 ?11.03 ?12.95	?15.75 ?17.64 ?17.22 ?17.91 ?17.10 ?16.46	?15.84 ?15.73 ?19.19 ?16.83 ?13.55 ?13.84	?16.20 ?18.18 ?15.29 ?16.61 ?18.58 ?17.53	?18.19 ?19.38 ?19.00 ?19.79 ?20.57 ?18.66	?11.60 ?1162 ?9.16 ???- ?14.15 ?10.94	?17.15 ?17.31 ?15.44 ?17.38 ?18.86 ?19.56	?15.00 ?16.41 ?13.74 ?12.02 ?14.31 ?14.38	?15.30 ?17.46 ?17.39 ?16.61 ?16.54 ?16.29
?2(n=6)		?16.72 ?16.77 ?16.57 ?19.08 ?18.64 ?18.16	?13.75 ?14.86 ?15.89 ?13.01 ?14.13 ?13.66	?19.81 ?17.88 ?19.22 ?19.83 ?20.63 ?17.72	?18.15 ?19.53 ?19.97 ?18.88 ?18.90 ?18.98	?14.15 ?11.47 ?10.73 ?12.71 ?12.24 ?12.29	?18.04 ?17.34 ?18.16 ?19.26 ?18.09 ?19.22
										?3(n=6)		?18.79 ?17.63 ?16.89 ?19.71 ?19.34 ?17.66	?13.18 ?14.03 ?13.55 ?14.73 ?15.73 ?15.33	?16.46 ?17.59 ?19.86 ?18.37 ?17.20 ?20.31	?17.71 ?17.14 ?17.28 ?19.12 ?19.32 ?19.13	?11.54 ?12.68 ?14.32 ?13.74 ?13.65 ?10.65	?12.12 ?17.78 ?16.85 ?16.30 ?14.15 ?18.19
Meansigma methods	?11.54	?17.67	?14.82	?18.18	?18.87	?12.21	?17.17	?14.31	?16.61
										Standard deviation	?2.1	?1.1	?1.5	?1.5	?0.9	?1.5	?1.8	?1.4	?0.9

Carrier residual quantity (microgram/capsules) in the capsule that table 5. matched group capsule and SFE-handle

Operation #	????1	??1E	??2	?2E1	?2E2	???3	??3E	???4	??4E
										?1(n=6)	?180.57 ?323.14 ?230.18 ?284.09 ?237.76 ?168.23	?207.7 ?174.1 ?153.9 ?215.4 ?157.7 ?222.3	?233.0 ?220.9 ?233.0 ?273.5 ?245.9 ?273.7	?66.3 ?130.7 ?55.1 ?76.2 ?74.8 ?85.0	?82.6 ?148.8 ?118.2 ?128.1 ?127.5 ?96.4	?300.4 ?288.3 ?365.5 ???- ?274.1 ?330.9	?133.2 ?73.6 ?101.6 ?81.5 ?99.2 ?97.1	?377.4 ?264.6 ?440.7 ?611.1 ?540.8 ?470.9	?272.1 ?275.5 ?213.1 ?326.1 ?262.1 ?285.5
?2(n=6)		?174.0 ?184.2 ?131.2 ?150.8 ?167.0 ?137.8	?266.8 ?195.2 ?183.5 ?322.9 ?314.0 ?262.7	?75.7 ?53.2 ?57.7 ?86.9 ?29.6 ?79.8	?115.7 ?88.9 ?165.6 ?94.3 ?146.2 ?147.8	?264.7 ?263.8 ?323.0 ?248.7 ?190.3 ?207.8	?147.1 ?149.5 ?70.5 ?167.7 ?129.7 ?86.2
										?3(n=6)		?142.4 ?123.4 ?244.8 ?110.9 ?161.0 ?203.3	?260.6 ?220.3 ?222.4 ?182.3 ?224.5 ?239.9	?70.4 ?67.1 ?134.6 ?51.5 ?52.0 ?25.4	?131.5 ?106.9 ?134.4 ?134.6 ?100.1 ?147.3	?280.0 ?219.1 ?223.4 ?219.9 ?288.5 ?325.8	?82.1 ?136.6 ?84.3 ?151.8 ?104.9 ?131.2
Meansigma methods	?237.33	?170.1	?243.1	?70.7	?123.0	?271.4	?112.7	?450.9	?274.4
										Standard deviation	?59.3	?62.6	?39.1	?28.2	?24.0	?49.1	?30.8	?121.7	?40.6

The fine grain quality (microgram/capsules) of the carrier that capsule produces that table 6. matched group capsule and SFE-handle

Operation #	??1	??1E	???2	??2E1	??2E2	???3	??3E	??4	???4E
										?1(n=6)	?191.3 ?120.0 ?175.2 ?172.1 ?161.1 ?191.6	?276.5 ?287.2 ?280.1 ?285.9 ?285.4 ?288.1	?179.2 ?188.1 ?230.5 ?191.3 ?186.5 ?169.4	?236.9 ?234.1 ?331.8 ?266.9 ?290.0 ?274.6	?285.6 ?312.9 ?281.7 ?305.0 ?315.2 ?289.9	?162.1 ?172.9 ?115.9 ???- ?187.1 ?133.8	?229.0 ?230.1 ?202.2 ?215.1 ?208.8 ?262.0	?328.5 ?334.5 ?293.2 ?273.2 ?277.8 ?287.5	?277.6 ?292.7 ?289.4 ?279.1 ?281.0 ?286.4
?2(n=6)		?99.8 ?286.6 ?289.5 ?312.4 ?308.2 ?303.5	?198.0 ?214.3 ?201.8 ?211.2 ?190.2 ?191.9	?263.4 ?241.9 ?457.3 ?277.2 ?286.0 ?247.3	?294.6 ?315.4 ?317.3 ?305.7 ?312.7 ?293.0	?190.6 ?142.9 ?130.9 ?162.7 ?156.4 ?158.3	?224.7 ?216.0 ?238.1 ?225.6 ?209.9 ?234.1
										?3(n=6)		?302.2 ?292.0 ?275.1 ?311.4 ?305.3 ?273.8	?154.5 ?170.2 ?171.2 ?189.5 ?205.6 ?193.8	?220.2 ?240.8 ?266.8 ?250.1 ?235.4 ?270.6	?290.6 ?264.9 ?266.1 ?302.3 ?304.9 ?323.7	?156.0 ?169.2 ?195.6 ?182.5 ?180.2 ?132.9	?140.8 ?197.5 ?219.2 ?201.0 ?182.3 ?240.2
Meansigma methods	?168.6	?292.4	?191.0	?271.7	?299.0	?160.6	?215.4	?299.1	?285.0
										Standard deviation	?26.5	?36.8	?18.3	?53.2	?17.0	?23.3	?26.3	?26.0	?6.55

In the matched group capsule, have the highest FPM and minimum residual quantity from the capsule (lot number 4) of the B of manufacturer.From the FPM of the capsular FPM of the matched group of lot number 2 near lot number 4, but the former residual quantity is obviously higher.

Residual quantity in the capsule of handling from the SFE-of the A of manufacturer is than low 2 to 4 times of the residual quantity in its corresponding matched group capsule.Minimum medicine and lactose residual quantity appear in the capsule of lot number 2.The medicine FPM of the lot number 2 that SFE handles also has repeatability, and its amount is 18.5 micrograms (account for accumulated dose 40%).The degree that reduces drug residue because of SFE in lot number 4 capsules is lower than other capsular reasons and is the residual suitable small amount of drug of matched group lot number 4 capsules; Yet, be different from the matched group capsule from lot number 4 of residual quantity scope in 2.2 to 7.8 micrograms, from a collection of residual quantity through extractive capsule in 3.8 to 5.1 micrograms.Therefore the capsule handled of SFE-has than the more uniform residual character of the capsule that is untreated, and is not subjected to its residual property effect, so SFE can be used for determining capsule character, not influenced by its source.

Table 3 and 4 shows that all capsules all can be handled through SFE, make average drug residue in 2.0 to 5.0 micrograms (4 to 11%) scope, and FPM is not influenced by capsule lot number and capsule manufacturer in 16.5 to 19.0 micrograms (36 to 41%) scope.In 4.5 to 10.5 micrograms (10 to 23%) scope, and mean F PM is in 12.0 to 15.0 micrograms (26 to 33%) scope compared to the capsular average drug residue of corresponding matched group for this point.The capsular drug residue of matched group is higher than the capsule through extraction, and this result proves that the SFE method weakens capsular drug residue ability greatly.As expected, lower drug residue is followed the corresponding raising phenomenon that FPM occurs in the SFE capsule.Merging reaches 3.5 ± 0.9 micrograms and 17.7 ± 0.9 micrograms respectively through the total residue and the FPM of the lot number 1 to 4 of extraction.Therefore, merge through the standard deviation of the residual quantity of extractive capsule or FPM all low.

Table 5 with 6 and Figure 15 and 16 show that in the carrier residual quantity of extractive capsule, the capsular residual quantity that SFE-handles is far below the matched group capsule, and the capsule through extracting produces the carrier FPM that carrier FPM is produced usually above the matched group capsule.In each batch capsule, the repeatability of capsule in extractive capsule and the carrier residual quantity between the capsule is higher usually.Except the carrier FPM of lot number 4 was unaffected basically, remaining carrier FPM was higher in extractive capsule.Therefore, carrier residual quantity and carrier FPM are subjected to just influencing of SFE processing.

The result that drug residue between capsule and the capsule and the repeatability of FPM are strengthened because of SFE extractive capsule method more is shown in detail in Figure 17-20, wherein combines lot number 1 to 4 all data.Figure 17 and 18 the explanation when capsule when SFE handles, drug residue reduces significantly, and the repeatability of drug residue is strengthened significantly.The variation of the capsule Chinese medicine residual quantity through extracting is in the scope of 1 to 6 microgram, and the variation of matched group capsule Chinese medicine residual quantity is in the scope of 2 to 15 micrograms.Figure 19 and 20 explanations are with supercritical CO ₂Extractive capsule can be strengthened medicine FPM and repeatability thereof.Usually within ± 2 micrograms, not influenced by the capsule lot number through medicine FPM that extractive capsule produced.The matched group capsule is then observed bigger variation.Similar stiffening effect to repeatability also appears on the carrier.

The above results comprises that the residual quantity of the chromatography of capsular hardness measurement, extract and residual matter, capsular SEM and medicine and powder and FPM prove jointly that the SFE method can extract the lubricant material part that mainly causes height drug residue and indefinite dosage, and to not infringement of capsule.The capsular extensive SFE of driving fit

The design of this research is that proof the present invention can be used for handling extensive quantity.Get the different lot number capsules that are closed state and install in the cotton bag that separates, tie up with plastic ties respectively.Cotton bag is added in the 80L cylindrical vessel more continuously, adopts supercritical CO ₂, working pressure swing method (2,500 to 1,500psig, 35 ℃) extraction.Each cotton bag contains 15,000 capsules of having an appointment.About 105,000 capsules of each extraction are operated and are close to 315,000 capsules 3 times.Commercial scale quantity then can reach millions of capsules.

Use industrial loading machine then, load several batches of capsule and corresponding matched groups thereof through extraction with the above-mentioned I.B./lactose powder mixture of different batches.Recently make 10 groups of I.B./lactose capsule altogether by 3 batches from capsule (1,3 and 5) and 1 as one of A of manufacturer from the general capsule (lot number 4) of the B of manufacturer.Capsule is regulated in the 53.3%RH environment and is adapted to, and uses Anderson C.I. to analyze drug residue and FPM then.The analytic process of each capsular medicine and carrier residual quantity all repeats to carry out 10 times in every batch.In each individual stage of C.I., analyze medicine and the powder collected by in 10 continuous C.I. operations.Therefore 10 capsular inclusions can accurately measure collected powder of each stage to all having distributed the capacity powder on preceding separator and 8 sublevel plates.

Originally studies confirm that, utilize the method for SFE extractive capsule scalable to a large amount of capsular scales in order to reduce powder residual quantity and raising FPM.All all than the residual less powder of its corresponding matched group capsule and produce higher dose and carrier FPM, are not subjected to the influence of lactose batch and I.B. batch through capsules of extraction.This result of Figure 21 to 24 explanation I.B..Also can obtain similar results by lactose.

Figure 21 points out, the capsule of handling through SFE is not subjected to the influence of capsule lot number, medicine lot number or carrier lot number than the residual more a spot of medicine of its corresponding matched group capsule.The lot number that is combined, the capsule Chinese medicine residual quantity distribution of handling through SFE is narrow (1.5 to 3.5 micrograms are to 2.5 to 5.5 micrograms) than the distribution of matched group capsule residual quantity.Capsule and the capsular average residual allowance of matched group that SFE handles reach 2.6 ± 0.6 micrograms and 4.5 ± 1.0 micrograms respectively.As laboratory scale research, still be minimum drug residue from matched group and the drug residue in the SFE processed group capsule of the B of manufacturer.

Figure 22 shows that the capsule that SFE-handles produces the more medicine FPM of a large amount than matched group capsule, is not subjected to the influence of capsule lot number, medicine lot number or carrier lot number.The FPM that capsule produced that handles from the capsule of the B of manufacturer and corresponding SFE thereof is usually a little more than the FPM that capsule produced of the A of manufacturer.The FPM almost constant (16.7 to 19.2 microgram) through the extractive capsule generation from the A of manufacturer is not subjected to the influence of capsule lot number, medicine lot number or carrier lot number.Otherwise the capsular FPM of matched group then changes between 13.0 to 17.5 micrograms.In a word, merge all capsules, reach 18.5 ± 1.7 micrograms and 14.8 ± 1.5 micrograms respectively by the capsule of SFE-processing and the mean F PM of matched group capsule generation.

Figure 23 and 24 illustrates respectively in the capsule of matched group capsule and SFE-processing, the difference of the repeatability of the drug residue between capsule and the capsule.Matched group capsule Chinese medicine residual quantity changes between 1.0 to 10.5 micrograms.On the contrary, the capsule Chinese medicine residual quantity excursion handled of SFE then narrow many (1.0 to 5.6).Therefore the performance of capsule aspect drug residue of SFE processing is all similar, is not subjected to the influence of capsule lot number.Therefore shown in the laboratory scale study, drug residue has higher repeatability, and therefore can be reached the drug dose of higher repeatability by the capsule that SFE-handles than matched group capsule.Use supercritical CO ₂Extraction medicine, carrier, and the effect of drug powder: result and analysis

Carry out the extraction research that drug powder is formed, whether be subjected to supercritical CO with the sticking property of measuring carrier ₂The influence of the impurity on the extraction particle surface.This technology is potential to be made the evenly surperficial of carrier and drug particle and have repeatability, therefore can improve the repeatability and the yield of fine grain quality.

Loaded and sealed capsule also can use supercritical CO ₂Extraction.This practice provides another kind of available SFE method to handle the capsular probability of having loaded drug powder.The SEF of lactose, medicine and mixture of powders

Lactose and I.B. are divided in 2, under 500psig and 35 ℃, with CO ₂Dynamic extraction 2 hours.Observe these two kinds of extractions and all do not cause detectable quality to run off, and detect its size and equal no change of overall appearance by the SEM microphotogram of lactose, this shows lactose and I.B., and the two all is suitable for the SFE processing.Therefore SFE can extract the impurity of these two kinds of materials, and does not influence preparation in fact.Impurity is trace normally, and therefore dissolves among the SCFs, as: CO ₂To being common in the impurity of the analogous protein in the lactose, when carrying out its extraction, has necessary pressurize to 10, about 000psig.

Table 7 and 8 our discovery results of explanation.The drug powder that is formed by the lactose through extraction is opposite with the matched group lactose that manufacturer is supplied, and the former has higher FPM.During the extraction lactose, the powder residual quantity is not caused significant change.Therefore residual quantity only is decided by capsule character, and the surface nature of lactose is then very important to the adhesion strength of carrier to measuring medicine.Therefore the lactose extraction provides the method for a kind of FPM of control.After capsule is regulated in 53.3%RH and adapted to, as if can improve FPM slightly and reduce residual quantity.Table 7. lactose extraction is mixed with medicine lot number 2 by lactose lot number 1 with the influence of FPM medicine and carrier residual quantity and forms drug powder.The medicine powder is filled in the capsule lot number 5 again

Condition	Medicine FPM (microgram/capsules)	Drug residue (microgram/capsules)	Carrier FPM (microgram/capsules)	Carrier residual quantity (microgram/capsules)
					?uL+uC	????10.9	????9.9	????147.7	????256.9
?uL+eC	????15.0	????4.4	????176.0	????129.9

?uL+eeC	????16.0	????2.8	????178.9	????83.7
					?eL+uC	????13.2	????8.7	????175.5	????206.2
?eLeC	????16.1	????2.9	????182.0	????92.5
					?eL+ecC	????17.1	????3.2	????213.7	????116.2

U: be untreated; E: through extraction; C: capsule is adjusted under 53.3%RH; C: capsule; L: lactose table 8. mixture of powders extraction is mixed with 2 and medicine lot number 1 by lactose lot number 1 with the influence of FPM medicine and carrier residual quantity and forms drug powder.Powder is filled in the capsule lot number 5 again

The condition of lactose and lot number	Medicine FPM (microgram/capsules)	Drug residue (microgram/capsules)	Carrier FPM (microgram/capsules)	Carrier residual quantity (microgram/capsules)
					????uB1	????14.1	????4.9	????223.1	????153.0
????eB1	????13.0	????4.9	????282.0	????127.6
					????uB2	????14.3	????4.5	????201.3	????142.3
????eB2	????14.0	????5.2	????194.8	????170.7

UB: untreated mixture; EB: treated mixture

The extraction of drug powder (being blended medicine and carrier) does not have any influence to medicine FPM or residual quantity.The sticking property that FPM is not influenced expression medicine and carrier does not change because of extraction process.Because we find that the lactose surface is subjected to the influence of SFE process, and contain through the FPM of mixture of powders of the lactose of extraction different with the FPM of the mixture of powders that contains the matched group lactose, therefore we conclude that the extraction of mixture does not influence the surface adhesive between medicine and the carrier.Therefore, the attachment zone between medicine and medicine or the carrier is not influenced by extraction.This means that again attachment zone is not subjected to CO ₂Effect, or the interaction force between medicine and medicine or the carrier is higher than CO ₂Dissolving power to the carrier surface composition.Loaded and sealed capsular SFE

Get 4 batches from the be untreated capsule of preparation merchant A ( lot number 1,5 and 6) with B (lot number 7), load above-mentioned I.B/ lactose powder mixture, driving fit is also sealed, adopts the extraction of pressure oscillating extraction down in 35 ℃ then.Measure then through the capsule of extraction and corresponding matched group thereof and load the two medicine and carrier FPM and residual quantity of capsule.Owing to extract lubricant in the presence of drug powder, so the powder that some lubricant through extracting may be distributed in capsule reaches between the supercritical phase mutually.If the lubricant that is adsorbed on the powder should bring out particle coacervation, and during the extraction when not getting rid of FPM fully, then can use and reduce FPM.Therefore, may need the extraction long period, to guarantee the lubricant in complete extractive capsule and the powder.

The residual quantity and the FPM of powder in these capsules of table 9 explanation.Usually, the capsular powder residual quantity (especially carrier residual quantity) through extraction is lower than the matched group capsule.Except the FPM of capsule lot number 1 has the decline slightly because of extraction process, other FPM then do not strengthen because of extraction process or do not change, and this proof extracts lubricant from sealed capsule.The lot number that is combined, untreated capsule Chinese medicine FPM reaches 16.0 micrograms, and is reaching 17.1 micrograms in the capsule of extraction.Be untreated or the drug residue in extractive capsule low and substantially the same (being respectively 4.3 and 4.4 micrograms).Therefore studies have shown that originally that the lubricant in sealed and the capsule loaded can extract through SFE, produces the preparation of common higher FPM and low powder residual quantity.The capsular SFE that table 9. has been loaded: medicine and carrier residual quantity are mixed the formation drug powder with the lactose lot number 2 that influences of FPM with medicine lot number 1

The capsule lot number	Medicine FPM (microgram/capsules)	Drug residue (microgram/capsules)	Carrier FPM (microgram/capsules)	Carrier residual quantity (microgram/capsules)
					????6	????15.1	????4.7	????208.4	????122.1
????e6	????14.7	????4.6	????182.7	????97.0
					????1	????15.5	????5.6	????201.4	????186.4
????e1	????13.6	????6.1	????159.1	????66.6
					????5	????14.3	????5.5	????201.3	????142.3
????e5	????18.5	????4.4	????237.8	????113.3
					????7	????19.1	????2.5	????256.0	????77.6
????e7	????21.7	????2.4	????263.6	????97.6

U: be untreated; E: through extraction

It should be noted that carrier residual quantity in the untreated capsule is far above the carrier residual quantity in extraction carrier (132.1 micrograms are to 93.6 micrograms).This expression through the extraction lubricant preferentially attached to drug particle on so that during sucking as easy as rolling off a log sticking on the capsule wall.Really, I.B. is an alkaline matter, and more strong with the stearic acid and the interaction of fatty acid through the extraction that are contained in the lubricant.This phenomenon also be interpreted as what through the extraction the little amplitude of capsule Chinese medicine residual quantity be lower than undressed, though lubricant is got rid of from capsule.Lactose is a kind of acidic materials, so it interacts consumingly unlike I.B. and the lubricant material through extracting.

Then prove the method for lubricant in the SFE method extractive capsule.This method can be used for extracting the lubricant material in opening capsule, driving fit capsule, sealed capsule or sealed and the capsule loaded, and the capsule outward appearance is not had physical property or chemical lesion.The lubricant extraction has shown can reduce medicine and carrier residual quantity, increases medicine FPM, and improves the repeatability of residual quantity or FPM.This method also shows applicable to the moisture content in extractive capsule, medicine or the carrier or other impurity.

The SFE of driving fit capsule, opening capsule, sealed capsule, medicine or carrier extraction can be carried out in 0.6 to 1.4Tc temperature range, the wherein critical temperature represented with K of Tc, and pressure is in 0.5 to the 100Pc scope.Therefore can use the SCF that is critical state or supercriticality.The mode that extracts can directly be carried out; By the mixer inclusions, material to be extracted is contacted with SCF; Make material to be extracted and SCF fluidisation; Or utilize the SFE of pressure oscillating.Be preferably in 1.0 to 1.1Tc temperature range and 1 to the 10Pc scope and extract.If use CO ₂During extraction, preferred condition is 31 to 90 ℃ and 1,070 and 10,000psig.Also can use CO ₂Or any other suitable SCF, comprise sulfur hexafluoride, nitrous oxide, fluoroform, ethane, ethylene, propane, butane, iso-butane, and composition thereof.Also can add organic solvent modified dose in any SCFs, to modify its solvent property, comprise ethanol, methanol, acetone, propanol, isopropyl alcohol, dichloromethane, ethyl acetate, dimethyl sulfoxine, and composition thereof.Preferably use the organic modifiers of suitable low concentration (0 to 20%).Similarly, the lighter-than-air gas that also can add different proportion is as N ₂, O ₂, He, air, H ₂, CH ₄And composition thereof in SCF, to change its extraction and transporting property.

Claims (17)

1. a processing is used to store the method for gelatin, cellulose and plastic capsule of the pharmaceutical preparation of dry powdery, wherein has the material that SCF can extract on this capsule surface, and this method comprises is exposed under the SCF capsule, to remove the material that extracts of SCF.

2. according to the process of claim 1 wherein, the material that can extract is to be used to make capsular die lubricant.

3. according to the process of claim 1 wherein, this capsule is an open type.

4. according to the process of claim 1 wherein, this capsule is the driving fit formula.

5. according to the process of claim 1 wherein that this capsule is sealed formula.

6. according to the method for claim 5, wherein load pharmaceutical preparation in this sealed formula capsule.

7. according to the process of claim 1 wherein that this capsule contains pharmaceutical preparation.

8. according to the process of claim 1 wherein that this SCF is a carbon dioxide.

9. according to the process of claim 1 wherein that this pharmaceutical preparation comprises lactose.

10. according to the process of claim 1 wherein that this pharmaceutical preparation comprises ipratropium bromide.

11. gelatin, cellulose or a plastic capsule that is used to store dry powdery pharmaceutical preparation, wherein this capsule has been exposed under the SCF, to remove the material that SCF can extract on the capsule surface.

12. a method that is used for dry gelatin or cellulose capsule, it comprises is exposed under the SCF capsule, to remove wherein moisture content.

13. one kind is used for dry method of having stored gelatin, cellulose or the plastic capsule of powdered drug preparation, it comprises makes capsule be exposed to SCF, to remove moisture content wherein.

14. a method of getting rid of surface impurity from employed one or more materials of pharmaceutical preparation, it comprises is exposed under the SCF this material, to get rid of the material that SCF can extract.

15. the noninvasive method of an extraction SCF extractable matter in container or porous matrix, it comprises this container or porous matrix is contacted under high pressure with SCF, reduces pressure then.

16. according to the method for claim 15, it also is included in and reduces after the pressure step of pressurize again.

17. according to the method for claim 16, wherein pressure is reduction and raises repeatedly.

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